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Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor.

Kurihara T, Warr G, Loy J, Bravo R - J. Exp. Med. (1997)

Bottom Line: One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues.CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates.These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

ABSTRACT
Chemokines are a structurally related family of cytokines that are important for leukocyte trafficking. The C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is a potent monocyte activator in vitro and has been associated with monocytic infiltration in several inflammatory diseases. One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues. CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates. To investigate the normal physiological function of CCR2, we generated mice with a targeted disruption of the ccr2 gene. Mice deficient for CCR2 developed normally and had no hematopoietic abnormalities. However, ccr2(-/-) mice failed to recruit macrophages in an experimental peritoneal inflammation model. In addition, these mice were unable to clear infection by the intracellular bacteria, Listeria monocytogenes. These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.

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Histopathology of  Liver from Listeria-infected mice.  (a) Minimal, focal inflammation in  a wild-type ccr2+/+ mouse (arrow).  (b) Severe, multifocal inflammation and necrosis in a ccr2−/−  mouse (arrows). (c) Higher magnification of a. The localized inflammatory focus contains macrophages  and neutrophils with necrosis of  individual hepatocytes (arrow). (d)  Higher magnification of b. The lesion is characterized by a central  core of coagulative necrosis containing neutrophils and cellular debris. A rim of degenerating and  necrotic hepatocytes that contain  abundant intracellular Gram-positive bacteria are located at the peripheral margin of the lesion. Insets  are sections stained with Gram stain.  Bars: (a, b) 200 μm; (c, d) 20 μm.
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Figure 4: Histopathology of Liver from Listeria-infected mice. (a) Minimal, focal inflammation in a wild-type ccr2+/+ mouse (arrow). (b) Severe, multifocal inflammation and necrosis in a ccr2−/− mouse (arrows). (c) Higher magnification of a. The localized inflammatory focus contains macrophages and neutrophils with necrosis of individual hepatocytes (arrow). (d) Higher magnification of b. The lesion is characterized by a central core of coagulative necrosis containing neutrophils and cellular debris. A rim of degenerating and necrotic hepatocytes that contain abundant intracellular Gram-positive bacteria are located at the peripheral margin of the lesion. Insets are sections stained with Gram stain. Bars: (a, b) 200 μm; (c, d) 20 μm.

Mentions: Since ccr2−/− mice are defective in the recruitment of new macrophages to the peritoneum, we determined if macrophage-dependent immunity to intracellular pathogens was also compromised in these mice. During the early phase of infection with the bacterial pathogen L. monocytogenes, the accumulation of blood-derived macrophages to the foci of infection are critical for controlling bacterial growth in infected organs (28). Groups of wild-type and homozygous mutant mice were challenged intravenously with 2,500 CFU of L. monocytogenes. After 5 d, when macrophages are essential for control of L. monocytogenes infection, all ccr2+/+ mice appeared active and healthy. In contrast, 33% of ccr2−/− mice died 4 d after infection and the remainder were moribund at 5 d. The bacterial burdens in the spleen, liver, and lungs were determined at day 5 (or at autopsy for ccr2−/− mice that died on day 4), and mutant mice had between 3–7 log–fold higher listerial titers than wild-type animals in all tissues (Fig. 3), confirming that CCR2 is required for listerial clearance. The level of sensitivity of CCR2-deficient mice to L. monocytogenes was similar to that seen in mice lacking the 55-kD tumor necrosis factor receptor (29, 30) or the interferon-γ receptor (31). At autopsy, livers and spleens from wild-type animals were of normal color but enlarged, while livers and spleens from mutant mice were of normal size but appeared mottled and off color. Histopathological analyses revealed minimal inflammatory foci comprised of macrophages, neutrophils, and individual necrotic hepatocytes in the livers of wild-type mice (Fig. 4, a and c). In contrast, severe, multifocal inflammation and necrosis were observed in the livers of ccr2−/− mice (Fig. 4, b and d). These lesions were comprised of a central core of coagulative necrosis containing neutrophils and cellular debris and a rim of degenerating and necrotic hepatocytes containing abundant intracellular bacteria. Severe, multifocal inflammation and necrosis was also observed in the spleens of ccr2−/− but not wild-type mice (data not shown).


Defects in macrophage recruitment and host defense in mice lacking the CCR2 chemokine receptor.

Kurihara T, Warr G, Loy J, Bravo R - J. Exp. Med. (1997)

Histopathology of  Liver from Listeria-infected mice.  (a) Minimal, focal inflammation in  a wild-type ccr2+/+ mouse (arrow).  (b) Severe, multifocal inflammation and necrosis in a ccr2−/−  mouse (arrows). (c) Higher magnification of a. The localized inflammatory focus contains macrophages  and neutrophils with necrosis of  individual hepatocytes (arrow). (d)  Higher magnification of b. The lesion is characterized by a central  core of coagulative necrosis containing neutrophils and cellular debris. A rim of degenerating and  necrotic hepatocytes that contain  abundant intracellular Gram-positive bacteria are located at the peripheral margin of the lesion. Insets  are sections stained with Gram stain.  Bars: (a, b) 200 μm; (c, d) 20 μm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199145&req=5

Figure 4: Histopathology of Liver from Listeria-infected mice. (a) Minimal, focal inflammation in a wild-type ccr2+/+ mouse (arrow). (b) Severe, multifocal inflammation and necrosis in a ccr2−/− mouse (arrows). (c) Higher magnification of a. The localized inflammatory focus contains macrophages and neutrophils with necrosis of individual hepatocytes (arrow). (d) Higher magnification of b. The lesion is characterized by a central core of coagulative necrosis containing neutrophils and cellular debris. A rim of degenerating and necrotic hepatocytes that contain abundant intracellular Gram-positive bacteria are located at the peripheral margin of the lesion. Insets are sections stained with Gram stain. Bars: (a, b) 200 μm; (c, d) 20 μm.
Mentions: Since ccr2−/− mice are defective in the recruitment of new macrophages to the peritoneum, we determined if macrophage-dependent immunity to intracellular pathogens was also compromised in these mice. During the early phase of infection with the bacterial pathogen L. monocytogenes, the accumulation of blood-derived macrophages to the foci of infection are critical for controlling bacterial growth in infected organs (28). Groups of wild-type and homozygous mutant mice were challenged intravenously with 2,500 CFU of L. monocytogenes. After 5 d, when macrophages are essential for control of L. monocytogenes infection, all ccr2+/+ mice appeared active and healthy. In contrast, 33% of ccr2−/− mice died 4 d after infection and the remainder were moribund at 5 d. The bacterial burdens in the spleen, liver, and lungs were determined at day 5 (or at autopsy for ccr2−/− mice that died on day 4), and mutant mice had between 3–7 log–fold higher listerial titers than wild-type animals in all tissues (Fig. 3), confirming that CCR2 is required for listerial clearance. The level of sensitivity of CCR2-deficient mice to L. monocytogenes was similar to that seen in mice lacking the 55-kD tumor necrosis factor receptor (29, 30) or the interferon-γ receptor (31). At autopsy, livers and spleens from wild-type animals were of normal color but enlarged, while livers and spleens from mutant mice were of normal size but appeared mottled and off color. Histopathological analyses revealed minimal inflammatory foci comprised of macrophages, neutrophils, and individual necrotic hepatocytes in the livers of wild-type mice (Fig. 4, a and c). In contrast, severe, multifocal inflammation and necrosis were observed in the livers of ccr2−/− mice (Fig. 4, b and d). These lesions were comprised of a central core of coagulative necrosis containing neutrophils and cellular debris and a rim of degenerating and necrotic hepatocytes containing abundant intracellular bacteria. Severe, multifocal inflammation and necrosis was also observed in the spleens of ccr2−/− but not wild-type mice (data not shown).

Bottom Line: One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues.CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates.These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

ABSTRACT
Chemokines are a structurally related family of cytokines that are important for leukocyte trafficking. The C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is a potent monocyte activator in vitro and has been associated with monocytic infiltration in several inflammatory diseases. One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues. CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates. To investigate the normal physiological function of CCR2, we generated mice with a targeted disruption of the ccr2 gene. Mice deficient for CCR2 developed normally and had no hematopoietic abnormalities. However, ccr2(-/-) mice failed to recruit macrophages in an experimental peritoneal inflammation model. In addition, these mice were unable to clear infection by the intracellular bacteria, Listeria monocytogenes. These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.

Show MeSH
Related in: MedlinePlus